Resistance against bioactive principles that directly target the origin of a disease are widespread, and one or more of a number of known resistance pathways are at their origin. For example, the Glutathione-S-Transferase (GST) is a superfamily class of isozymes that constitute the main cellular defense against xenobiotics, including bioactive principle designed for the treatment of a disease. They catalyse the conjugation of endogenous glutathione (GSH) with the electrophilic groups of substrates, the first step in the mercapturic acid pathway that leads to elimination of toxic compounds. The overexpression of several subclasses of GST, namely GST-π r and GST-α, has been linked to the multidrug resistance phenomenon of certain anticancer drugs, such as cisplatin and adriamycin. More recently, GSTP1-1 (GST-π subclass) was found to mediate the c-Jun N-Terminal Kinase (JNK) signal transduction pathway, an important control of cell survival. It was found to have a significant affinity for the C terminus of JNK and therefore could potentially interfere with and suppress downstream induction of cellular apoptosis. Clearly, GST is a potential target for chemotherapeutic drug design, in order to inhibit resistance against anti-cancer drugs.
Ruthenium-based compounds have shown some potential as anticancer drugs. For example, U.S. Pat. No. 4,980,473 discloses 1,10-phenanthroline complexes of ruthenium(II) and cobalt(II) which are said to be useful for the treatment of tumour cells in a subject.
Some other ruthenium(II) and ruthenium(III) complexes which have been shown to exhibit antitumour activity are mentioned in Guo et al, Inorganica Chimica Acta, 273 (1998), 1-7, specifically trans-[RuCl2(DMSO)4], trans-[RuCl4(imidazole)2] and trans-[RuCl4(indazole)2]. Clarke et al have reviewed the anticancer, and in particular the antimetastatic, activity of ruthenium complexes: Chem. Rev., 1999, 99, 251-253. Also, Sava has reviewed the antimetastatic activity in “Metal Compounds in Cancer Therapy” Ed by S P Fricker, Chapman and Hall, London 1994, p. 65-91.
Dale et al, Anti-Cancer Drug Design, (1992), 7, 3-14, describes a metronidazole complex of ruthenium(II) ie, [(C6H6)RuCl2(metronidazole)] and its effect on DNA and on E. coli growth rates. Metronidazole sensitises hypoxic tumour cells to radiation and appears to be an essential element of the complexes of Dale et al. There is no indication that the complexes would be at all effective in the absence of the metronidazole ligand.
Kramer et al, Chem Eur J., 1996, 2, No. 12, p. 1518-1526 discloses half sandwich complexes of ruthenium with amino esters. Bennett et al, Canadian Journal of Chemistry, (2001), 79, 655-669 discloses certain ruthenium(II) complexes with acetylacetonate ligands. Oro et al, J Chem Soc, Dalton Trans, (1990), 1463 describes ruthenium(II) complexes containing -p-cymene and acetylacetonate ligands. WO 01/130790 discloses ruthenium(II) compounds and their use as anticancer agents. The compounds have neutral N-donor ligands and the resulting ruthenium complex is generally positively charged.
WO 02/102572 also discloses ruthenium(II) compounds that have activity against cancer cell lines. Again, the complexes are generally positively charged. Complexes are disclosed containing a bidentaie ligand which is a neutral diamine ligand.
Chen et al, J. Am. Chem. Soc., volume 124, no 12, 3064, (2002), describes the mechanism of binding of ruthenium complexes to guanine bases. The binding model requires NH bonds from a diamino ligand to be present in the complex for hydrogen bonding to the guanine base. Similarly, Morris et al, J. Med. Chem., volume 44, 3616-3621, (2001), describes the selectivity of ruthenium(II) complexes for binding to guanine bases.
Further references concerned with Ruthenium complexes for treatment of cancer are WO 06/018649, US 2006/0058270, US 2005/0239765.
Very few, if any, of the compounds and complexes of the prior art cited above have resulted in clinical phase studies, not to mention actual therapies. The reason for the poor performance of these principles are manifold and may be linked to toxicity problems or un-sufficient efficiency in treatment.
It is thus an objective of the present invention to explore new ways for treating cancer, for example based on work done in the area of complexes of transition metals.
It is a further aspect of the present invention to increase the activity and/or efficiency of therapies against diseases and in particular cancer. More particularly, it is an objective to reduce the resistance intrinsic to or developed against therapies, and in particular against resistance in cancer chemotherapies. By reducing resistance to bioactive principles against diseases an in particular cancer, it is hoped to increase the overall efficiency of the therapy. With increased efficiency, lower levels of the bioactive principle needs to be administered, which may further reduce side effects linked to the treatment.
Tumors of various kinds can be removed surgically, the most relevant problem of these cancers being the development of metastasis. It is thus an objective of the present invention to prevent and/or treat metastasis. In particular, it is an objective of the invention to assist the treatment for prevention and/or treatment of metastasis.